2-lower-alkyl-9alpha-halo-4-pregnenes



United States Patent 2,923,722 Z-LOWER-ALKYL-Qa-HALO-4-PREGNENES John A. Hogg and Frank H. Lincoln, Jr., Kalamazoo Township, Kalamazoo County, Mich., assignorsto The Upjohn Company, Kalamazoo,,Mich., a corporation of Michigan No Drawing. Application May 23, 1955 Serial No. 510,518

Claims. (Cl. 260397.'45)

This invention relates to novel steroids, more particularly to synthetic steroid hormonesyto novel steroid intermediates in the production of these synthetic steroids 'andthe process for their production. This application is a continuation-in-part of our copending application S.N. 485,318, filed January'31', 1955. 1

The novel synthetic steroid hormones of this invention, i.e., 2 lower alkyl 9a halo 11fi,l7m,21 trihydroxy-4-pregnene-3,ZO-dione and .21-esters thereof, and 2 lower alkyl 9m halo 1761,21 dihydroxy 4 pregnene- 3 ,l 1,20-- trione and esters .thereof especially the 2 methyl 90c fluoro compounds, possess outstanding mineralocorticoid, glucocorticoid and anti-inflammatory activity. They are useful in the treatment of inflammations of the skin, eyes and ears of humans and valuable domestic animals ,due to contact dermatitis, allergic reactions or other physiological malfunctions and many bacterial and fungal infections. ,The 2-lower-alkyl-9ahalo 11,53,17a dihydroxy 21 acyloxy 4 pregnene- 3,20-diones of the present invention, and intermediates produced in a process for their production, may be represented by the following formulae:

, CH3 C Hg '(IJH O- EIJOHQ' CHrO-fiCHa H of H .0 no? t? CHa-O-(il-- p c II o= 0,

CH3 CH3 (lJHf-OH CfHz-O-(fiCHa lower alkyl CH: '11) (H) I euro-( 0- Iv lower-alkyl 0: e- O:

wherein Ac is the acyl radical of a hydrocarbon oarboxylic acid containing from one to twelve carbon j-atorns, inclusiveyand X is a halogen having an atomic weight f n en to 3 in u i e, 3 ch or n -cor fluorine. nd X is a h gen ha ng a a mic weightirem 7.9 to 127, inclusive, i.e., bromine or iodine; lathefog- .mulae .-and pec fica ion, the t m f wer-alky mean containing from one to eight, carbonatorns, inclusive,

It is an object of the present invention to provide synthetic corticosteroids 2 -'lower,,- allgyl 9 halo- 1l[3,17a,21 trihydroxy 4 pregnene 3,20. dione @nd 21- esters thereof and 2 -"lower alkyl 9 312110- 17u,21 dihydroxy 4 pregnene 3,11,20 tr1one and 2l-esters thereof. Another object'is the provi qf steroid intermediates readily convertible, to these ynthetic steroid hormones. Still another object'isthe provision of a process for the production of these synthetic steroid hormones. Other objects will be apparentto those skilled-in the art to which this invention upertains.

11B hydroxy 21 acetoxy 4,17(2 0) pregnadiene- 3-one (I) is converted to the novel syntheticrho of the present invention by the following reaction glyoxalation with dirnethyl oxalate to produce'a oxyoxalyl derivative (II); second, alkylation to pr the corresponding 2-1ower-alkyl-2 rneth-ogry-oxalyl.co p u d d, emova tt ,Z-QaIbQ Y H- mu o p ce h e -alky c mp nd V); f urth terification of the thus-produced 21-hydroxy compound to produce a 21 -esterified compound (V); fifth, oxidative hydroxylation of the A -double bond to produce a 2 lower alkyl 115,17 dihydroxy. 21 ac yl o; ;y- -4-pregnene-3,20-dione (VI), as disclosed incur copending application S.N.. 485,318, fil d, January ;31, 1955 sixth, dehydration of the 11a-hydroxygroupto produce the corresponding 9(11)-- dehydro compound I seventh, introduction of the bromohydrin groupwwith hypobromous acid to produce the corresponding s90;-

" ably acetoxy.

' alkyl-9a-fluoroacyloxy-4-pregnene-3,20-diones of the present invention i I one of these esters, preferably the 21-ace'tate', is productive of the corresponding 21-lower-alkyl-9a-halo-l15,1711, 21-trihydroxy-4-pregnene-3,20-dione (X, wherein the Ac group is replaced by a hydrogen atom).

The starting 11B hydroxy 21 acetoxy 4,17(20)- pregnadiene-S-one is prepared by reacting ll-ketoprogesterone with about a molar equivalent of sodium methoxide and about 2.75 rnolar equivalents of diethyl oxalate in benzene, brominating the thus produced sodium enolate with about two molar equivalents of bromine and reacting the brominated productwithscdiurn methoxide and methanol to produce methyl 3,11-diketo-4,

17(20)-pregnadiene-2l-oate. Ketalizing the 3-keto group with ethylene glycol followed by reduction with lithium aluminum hydride and subsequent hydrolysis of the ethylene glycol ketal group with aqueous acid is productive of 115,21 dihydroxy 4,17(20) pregnadiene- 3-one. 11p hydroxy 21 acetoxy 4,17 (20) pregnadiene-3-one is prepared by the reaction of the latter compound with the selected esterification agent, e.g., acetyl chloride or acetic anhydride in pyridine. The production of 11 3,21 dihydroxy 4,l7(20) pregnadiene-3- one and 21-esters thereof is disclosed in US. Patent 2,774,776.

Oxidation of a 2 lower alkyl 9a halo 1119,1711- dihydroxy 21 acetoxy 4 pregnene 3.20 dioue produces the corresponding 2 lower alkyl 9a halo- 17m hydroxy 21 acyloxy 4 pregnene 3,l1,20-

trione, wherein the llp-hydroxy group is replaced by an ll-keto group. These steroids also possess cortical hormone activity markedly different from the corresponding esters of 170:,21 dihydroxy 4 pregnene -'3,11, 20-trione. Especially outstanding among these compounds are 2 methyl 9a fluoro 17a,21 dihydroxy-4-pregnene-3J1,20-trione and the 21-esters there- 'of wherein the ester group is lower-acyloxy and prefer- These compounds possess a hormonal activity spectrum, e.g., mineralocorticoid, glucocorticoid and anti-inflammatory activity different from any of the natural or heretofore known synthetic adrenal cortical hormones. Their anti-inflammatory activity is of an especially high order of activity.

Substitution of another 2-lower-alkyl-11fi,17a-dihy- "droxy-21-acyloxy-4-pregnene-3,20-dione as the starting steroid in the reactions described above is productive of the corresponding 2-lower-alkyl-9u-chloro or fluoro- I 11p,17m-dihydroxy-21-acyloxy-4-pregnene-3,20-dione.

- The-novel 2-lower-a1kyl-9a-halo-1 1 fi,l7a,21-trihydroxy- 4-pregnene- 3,20-dione and 21-esters thereof (X) have a 'h'ighorde'r of physiological activity, and possess different activity spectrum than the adrenal cortical hormone hydrocortisone.

- mones of the present invention possess anti-inflammatory, glucocorticoid, and mineralocorticoid activity of a high order. Their surprising pattern of physiological activity is exemplified by the fact that 2-methyl-9a-fluoro-11 3,170:- .dihydroxy-Z1-acetoxy-4-pregnene-3,20-dione has both pro- The novel synthetic cortical steroid hornounced mineralocorticoid and anti-inflammatory activity.

For example, the 2-methyl-9a-fluoro synthetic cortical hormone of the present invention has a glucocorticoid activity about twenty to thirty times as great and an antiinflammatory activity, about 8.5 times as great as hydrocortisone and a mineralocorticoid activity about sixty times that of desoxycorticosterone acetate. The novel intermediates' VII to IX also possess a useful glucocorticoid and anti-inflammatory activity.

' The novel 2-lower-alkyl-9a-fluoroand Sec-chloro- 1l3,17a,21-trihydroxy-4-pregnene-3,20-dione and 2-lowerand -9a-chloro-1 16,17a-dihydroxy-2 1- can be used orally, topically or parenterally. Oral compositions'ofthe invention can be prepared and administered in the form of tablets, capsules, powders or liquid suspensions. Tablets for advantageousmucosal absorption can also be made using either polyethylene glycol as the diluent.

The novel 2-lower-alkyl-9a,fluoroand -9a-chloro- 1118,1701,21-trihydroxy-4-pregnene-3,20 dione and 2-loweralkyl-9a-fiuoroand -9a-chloro-1lB,l7a-dihydroxy-21- acyloxy-4-pregnene-3,20-diones of the present invention are especially useful as pharmaceutical compositions and mixtures, e.g., ointments, lotions, jellies, creams, aqueous suspensions, etc., for topicaluse. Examples of especially advantageous pharmaceutical compositions are listed below. Although the examples are to the 2-methyl-9afluoro 11/3,l7a,21 trihydroxy 4 pregnene 3,20 dioue and 2-methyl-9a-fluoro-ll5,l7a-dihydroxy-21-acetoxy-4-pregnene-3,20-dione, it is to be understood that molar equivalent amounts of the other 2-lower-alkyl homologues and corresponding -9u-chloro analogues of the present invention and 2l-esters thereof, respectfully, are substitutable therein.

The novel 2-methyl-9u-fluoro-1113,17a-dihydroxy-21- acetoxy-4-pregnene-3,20-dione is advantageously employed in a bland, non-irritating ointment base for use in the'treatment of topical inflammatory conditions. A suitable dermatological and ophthalmic ointment has the following composition:

lbs. I 20 percent wool fat USP 25 percent mineral oil USP 0.1 percent 2-methyl-9a-fluoro-llfi,l7a-dihydroxy- 21-acetoxy-4-pregnene-3,20-dione (micronized)-.. 0.5 White petrolatum USP, q.s.-ad 500 Incorporation of an antibiotic in the ointment, especially neomycin sulfate, has surprising therapeutic advantages each active ingredient potentiating and supplementing the useful properties of the other. Such an ointment is as follows:

lbs.

20 percent wool fat USP 100 25 percent mineral oil USP 125 0.6 percent neomycin sulfate (microatomized) 3 0.2 percent 2-methyl-9a-fluoro-1113,17a-dihydroxy- 21-acetoxy-4-pregnene-3,20-dione (micronized)..- 1

White petrolatum USP, q.s.-ad 500 In place of, or in addition to, neomycin sulfate, other antibiotics such as bacitracin, circulin, polymyxin B sulfate, gramicidin, streptomycin sulfate, dihydrostreptomycin sulfate, oxytetracycline, chlortetracycline, tetracycline, chloramphenicol and the sulfonamide's can be used to enhance the usefulness of the above ointments.

An injectable composition suited for suspending the compounds of the present invention having advantages in the treatment of Addisonian crisis-and shock is as follows:

Sodium citrate USP m 5.7 Sodium carboxymethylcellulose, low viscositymg 5.0

Plasdone (polyvinylpyrrolidone) mg 5.0 Polysorbate 80, USP ..mg 4.0 Sterile methylparabenUSP mg 1.5 Sterile propylparaben USP mg 0.2 2 methyl 9a fluoro 11fl,17a dihydroxy 21 acetoxy 4 pregnene 3,20 -dione mg. 5 .0 Water for injection, q.s.-ad cc 1.0

. Another composition: suitablefir injection: b g-award lowingcomposition': I Sterile micronized;2-rnethyl-9bz fluoro-1lflfl'louzl-tfi Thefpolyethylene glycol, sodium chloride,- Po'lysorb'ate 80 :and benzyl 1 alcohol are-dissolved 'in water and the .solil flout-sterilized by-"filtration: 1 Sterne"2 methyl 9-fluoro* 11B,176:;2l trihydroxy4 pregnene 3j20-dione isxth'enasep tically." mixed with the sterile vehicle arijd the whole' homogenized; i

The -following examples are illustrative -r'orstne process and products oft the 'presje'nt invention}. h'ut area-drop to' be construed as limiting;i.-- l t mom a: (\VII.)

A mixtureof onegrame(2:58 millimoles)*of mafia;

1'lfl,'1-7a-dihydroxy-'2l acetoxy4 pregriene 3;-20 dion 62 milligrams (two equivalents) of N-bromoace'tamidefand six 'milliliters of pyridine-'fwstirredfinthedark-"tor thirtyminutesi Th'e mixture gwas' cooled inanice-Wa'ter bath" and a'str'eam of-sulfurdioxide"wasdirectedonto-Hie' surfaceof the stirred mixture until a nega'tiVeKI-starehtest Wasobta'ined. Fifty milliliters of watefiwas then" Following the procedure described inExari'iple-lj substituting another 2*1 ester"of'a"2lower alk yl l 1337a,

closed'irr" our 'cop'eriding' application SEN; 485,;18, es'p' r: cially the 2-m'ethyl l 1B,17& dihydroxy-2l acyloxytpreg nene-3,20-diones wherein the acyl radical is-='that ofa hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, as the starting steroid in the reaction, there are" produced other ZI-estersIfOf i 2- methyl- 17:1,2 1 -dihydroxy-4',9 1'1 -pregnadiene-3,20- dione and 2-lower alkyl homologues thereof.

pregnene-3,20-dione'( VIII-.)

To a 'stir'red'solution 50.50 gram (j1;24millimole')" of." 2-methyl-17u-hydroxy-2l acetoxy-4,9(1 1 'pregnadiene-f 3,20-dione in twenty milliliters lot.- methylene' chloride was added a solution ofone milliliter of 71 percent per chloric acid, in ten milliliters'of 'water, and 2 06'm'illigrams (1.49 millimol) of"N bromoacetamidedn fifty milliliters of tertiary butyl. alcohol. The-solution wasv maintained at" room temperature for fifteen minutes" and then mixed with a solution of0l25 gram of sodium sulfite in' twelve milliliters of. water. The' mixt'ure was distilled at reducedpressure 'until'the residual solution Became)"cloudy The"? product was" then. precipitatedi herefrom bythe addition orroo millilitersat a mixture" amaze of "ic'er'and j waterf white, crystalline precipitate; of 2Zmethyl 96t-bromo-1 1 B, 17q-dihydroxy-2 l-acetoxy-4-pregnene 3,20-dione was filtered, washed with-water and. thendried;'at roomitemperature under vacuum. The dry productiweighed 0.57 gram, a yield of 92.2' percent of thei'theoretic aLand melted at to degrees centigra'de; A 'satnplerecrystallized' from .a mixture of acetone andSlcellysol've B hexane hydrocarbons. melted at 128. to 131. degrees"'centigradei and. hadthe. analysis below."

from;onectotwelvecarbon atoms, inclusive, as. the starting steroid: inrthe. reaction, thereare produced other 21-- ester's of} 2-methyl-.9a--'bromo-1lfi,1.7a,2'1-trihydroxy-4'- homologues.

pregnene:-3-,20dione thereof.)

and 2-lower.-alkyl* I EXAMPLE. 3 v 2 methyl Sldl fiwxido-l 7a-hydroxy-21 acet'oxy-4 pfe'gnne-BQO-dione (IX A mixture /of;0.47-,gram (0.95 millimole) of 2-methyl- 9i1vbfOmO-11[3,170L-dihYdI'6XYr21. acetoxy 4-pregnene-3,

20-dione,10.47"gramof. anhydrous potassium acetate and twenty' milliliter's of acetone. was heated at its refluxing, The cooled mixture was) poured into water and} then extracted. with methylene.

temperature 'forfiive. hours.

chloride. The methylene chlorideextract was dried and then' 'poured over a columnof 25 gramsof Florisil synthetic magnesium. silicate. The column was developed with Skellysolve B hexane hydrocarbons containing increasing proportions ofacetone. The Skellysolve B plus ten percent acetone eluates contained 0.29 gram, a yield ofz'75 percent-of the theoretical, of 2-methyl-9': ll-fl-oxido 17a-hydroxy-21-acetoxy-4-pregnene 3,20 dione which, when recrystallized from a mixture of acetone and Skellysolve-B; was-obtained ascolorless plates me'lting at 185 to 188 degrees-centigrade; having an [mi of plus-49' degrees in chloroform, and having the analysis below. Calculated forfCg H O ::C,*69L20; H, 7.75; Found: C; 6.9.28; H, 7.90. i V

Followingthe' procedure described' in Example 3, but substituting another ZI-ester of a 2-lower-alkyl-9u-bromonene3;20'-dione wherein'the'acyl radical is that of'a carhoxylic acid-named'in the' paragr'aph following Example 5gespec'ially tliose' of hydrocarbon carboxylic acid conmining-from onefto twelve carbon atoms, inclusive, as

the starting steroid in the reaction, there are producedother 7 2 1'-esters of' 2*methyl-9211--/3-oxido l7a,2l-dihydroxy-4-pregnene-3,20-dione and 2-lower-alkyl homol'ogues thereof.

" EXAMPLE; 4' 2 mthylr9bz-flilor0 1] '13,] Za-dz'hydroxy-ZI -ace'tqxy-4- pr'egnne-iZO-diorie (X) A---solution of 1.07 grams. (2.57. millimoles) of 2- methyl -'9: 11-fl-oxido l7mshydroxy- 21 acetoxy- 4-pregnene:-'3',20-dione in milliliters of methylene chloride was 'cotic'entra'ted to a volume of fifty milliliters by dist-illationr- To the-concentrated solution at room temperature wasadded' five milliliters of 48' percent hydrofluoric acid'and 0.5 milliliter of'7'1 percent'perchloric acid. The mixture wasstirred vigorously for six hours and then poured into an excessof 'cold aqueous five percent sodium bicar'honate'solution; Theimethylene chloride, layer was separated; driedwith anhydrous sodium sulfate arid-tlictt poured over a column of lO O grams of Eloris il synthetic magnesium silicate. The column was f developed with 200 milliliter portions of Skellysolve B plus ten percent acetone. The eighth through sixteenth eluate fractions contained 0.61 gram of 2-methyl-9a-fiuoro-l11 ,17a-dihydroxy-Z1-acetoxy-4-pregnene-3,20-dione which after crystallization from a mixture of acetone and Skellysolve B melted at 218 to 222 degrees centigrade with decomposition. A portion recrystallized fromthe same solvent melted at 225 to 228 degrees centigrade with decomposition, had an [ed of plus 156 degrees in dioxane, a'

. ct r E 15,850, and the analysis below: J

Calculated for c ,H FO C, 66.03; H, 7.62; F, 4.35. Found: C, 65.62; H, 7.54; F, 3.87. I a

Following the procedure described in Example 4, but

substituting another 2l-ester of a 2-lower-alkyl-9zll-fioxid'o-l7a,2l-dihydroxy-4-pregnene-3,ZO-dione, e.g., a 2- nene-3,20-dione wherein the acyl radical is that of an organic carboxylic acid named in the paragraph following Example 5, especially those of a hydrocarboncarboxylic acid containing from one to twelve carbon-atoms,

inclusive, as the starting steroid in the reaction, there are e.g., one named above, in thereaction with hydrogen chloride is productive of other 2-methyl-9a-chloro;l1p, 17u-dihydroxy-21-acyloxy-4-pregnene-3,205diones.

EXAMPLE 5 2-methyl-9a-fluoro 115,1 70:,21 trihydroxy 4pregnerie- 3,20-dine A solution of 437 milligrams of 2-methyl-9afluoro- 11,6,l7a-dihydroxy 21-acetoxy-4 pregnene-3,20-dione is freed of oxygen by bubbling nitrogen therethrough. A solution of 404 milligrams of potassium bicarbonate in four milliliters of water is similarly freed of oxygen. The two solutions are mixed at a temperature between eighteen and twenty degrees centigrade in a nitrogen atmosphere. The mixture is stirred at room temperature for five hours while protecting it from atmospheric oxygen with nitrogen. vAt the end of this time the solution is neutralized with glacial acetic acid. The neutral solution is concentrated by distillation at room temperature and reduced pressure and thenchilled in a refrigeratorfor sixteen hours. The precipitated 2-methy1 -9a-fluoro-11B, 170:,2l-trihydroxy-4-pregnene-3,20-dione is .tiltered and dried.

2-methy1-9e-fiuoro-11/3,l7a,21-trihydroxy 4-pregnene- 3,20-dione. is converted toother 2-methyl-9a-fluoro-ll 9, 17a. dihydroxy-Zl acyloxy-4 pregnene-3,20 diones by esterification of the 21-hydroxy group, e.g.,by" reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the presence of an esterification catalyst, etc. Examples of Z-rnethyl- 9oc-fit10f0 1113,17uc dihydroxy 21-acyloxy 4-pregnene- 3,20-dione prepared include those wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 2-methylbutyric, B-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, the optically active abietic, m-ethylisovaleric, an acyclic acid, e.g., 3B-hydroxycholanic, 3/3-hydroxyetiocholanic,

eyclopropylideneacetic, a cycloaliphatic acid, e.g., cyclo-.

fifth??? pentylfvqtmic... cyelopentylacetic,. zp-cyclqpentyipropionic,

" cyclohxylformic, cyclohexylacetic, p-cyclohexylpropionic,

zoic, ethylbenzoie;2,4,6 trimethylbenzoic, 2,4,6-triethylbenzoic, -a-naphthoic, 3-methyl-ii naphthoic, an aralkyl to water soluble, e.g., sodium-,- salts) e.g., succinic, glu- -taric, =d methylglutaric, fi-methylglutaric, flfi-dim ethylglu- .taric, adipic, pimelic,. suberic, a hydroxyacid, e.g., gly- ,colic,'-l'act-ic', citric, tartaric, d-malei'c, d-glyceric, mannonic, ,gluconic, salicyclic, an ,aminoacid, e.g., glycine, diglycolamic, ,triglycolamic .methylglycine, dimethylglycine, ,diethylglycine, para-aminosalicyclic, para-aminobenzoic, other heterosubstituted acids, e.g., ethylmercapto- ,acetic, benzylmercaptoacetiq; cyanoacetic, chloroacetic, i. .fillOroaee tic, trichloroacetic,. trifiuoroacetic, thioglycolic,

. methylacetylmercapto,

, pregnene- 3,20-dione.

2,3,4-trimethoxybenzoic, a-naphthoxyacetic, B-pyrrolidyL- propionic, carbamic acids, e.g., carbamic acid, phenylcarbamic, n-butylcarba'mic, dime'thylcarbamic, diethylcarbamic, '.allophanic, or a lieterocyclic acid,-e."g., B furylcarboxylic, N-methylpyrrolidyl-Z-carboxylic, a-picolinic,

25 indoleQ-carboxylic, 6-hydroxyindolyl-5-acetic, N-methylbh ir oxy ysergic, pyrro lyl-2-Icarboxylic, or other acyl acid,

' Alternatively, e 21- hydroxy giroup of the Z-methyl- 1 1fl,17a,21-trihydroxy'4,l7 (20) pr'egnadiene-,3-one-. can be converted to another 2l-derivative, leaving the remainder of the molecule unchanged. I Examples of such 21-deriva- Itives are ZI-ethers, e.g., 2 l,-methoxy, ethoxy, benzyloxy, propoxy, a tetrahydropyranyloxy, (/3 carbethoxy f3- cyano) ethyl enoxy, ,8,,B-dicarbethoxyethenyloxy, ,fl-ketocyclohexenyloxy, fl-trichloro-u-acetylethoxy, chloromethoxy, dimethylmethoxy, diethylmethoxy,v dimethylethoxy, diethylethoxy, 2l-thioesters, e.g.,acetylmercapto, fl-cyclopentylpropionylmercapto,- triethylacetylmercapto,- tri' propionylmercapto, 21 thione esters, e.g., thioacetyloxy, .thiopropionyloxy, I thio-B-cyclm pentylpropionyloxy, thiotriethylacetyloxy, thiotrimethylacetyloxy, imido derivatives of acetyl esters, e.g., acetimido-oxy, 21-esters of mineral, acids, e.g., 21 phosphate, 21 -sulfonate, '21-sulfinate, ZI-methylphosphate, .Zl-methylsulfonate, 2l-methylsulfinate, 21-bromo, .fluoro and 21- chloro, esters of the carbonic acids, e.g., ZI-carbonate, 2l (triethoxy)methoxy, 2l-sulfonyloxy, e.g., 21-paratoluenesulfonyloxy, etc. I

Following the procedure of Example 5, but substituting 2-methyl-9a-chloro-l1p,17ri-dihydroxy-2l-acetoxy 4- pregnene-3, 20-dione as the starting steroid, there is thusproduced Z-methyl 9a-chloro #115,170521 trihydroxy-4- EXAMPLE 6" tion' is thereafter allowed to rise toeighteen degrees centigrade over a period of one hour. The excess chromium t'rioxide is destroyed by the addition of an aqueous sodium s'ulfite solution, and the product then extracted from the reaction mixture with three fifteen-milliliter portions of ether which are thereafter combined,

' sulfite. The. ether is then removed by evaporation. The

washed with water, and dried over anhydrous sodium residue consists essentially of 2-methyl-9a-fluoro-l7ahydroxy-Zl-acetoxyf4 pregnene,i 1 ,20;trione,. which is 9 purified by chromatographingovefa column of ten grams of Florisil synthetic magnesium-silicate. Developing the column with Skellysolve B hexane hydrocarbons containing increasing proportions of acetone elutes essentially pure 2-methyl-9a-fluoro-l7a-hydroxy-21-acetoxy 4-pregnene-3,1 1,20-trione from the column.

Similarly, other 21-organic carboxylic acid esters of 2 lower-alkyl-9u-fiuoro-17u-hydroxy-2l-acyloxy-4-preg nene-3,l1,20-trione, preferably" wherein the lower-alkyl group is methyl, are prepared by oxidation of the corresponding ester of 2-lower-alkyl-9u-fluoro-17a,2l-dihydroxy-4-pregnene-3,ZO-dione, preferably the esters named in the paragraph following Example 5, especially those wherein the acyl radical is that of a hydrocarbon carboxylic acid containing frornone to twelve carbon atoms, inclusive. Substituting the corresponding 9ix-chloro compounds, preferably 2-methyl-9a-chloro-l1,8,17a-dihydroxy-21-acetoxy-4-pregnene-3,20-dione,- as the starting steroid in the reaction described above, is productive of the corresponding 9a-chloro-11-keto compounds, preferably 2-methyl-9a-chloro-17uhydroxy21-acetoxy-4-pregacne-3,1 l,20-trione.-

The examples hereinbefore describe the preparation of 2-methyl-9a-fluoro-11/3,17a,21 trihydroxy 4 preguene-3, ZO-dione, Z-methyl 9a chloro-1'lfi,17a,21-trihydroxy-4- pregnene-3,20-dione and ZI-esters and other 21-derivatives thereof-and the corresponding ll-keto analogues thereof. Substitution of another 2-lowera1kyl-l l 6,17adihydroxy-2l-acyloxy-4-pregnene-3,20-dione, e.g.,- those disclosed in our copending application 485,318, as the starting steroid in" Examples- 1, or substituting 2-loweralkyl homologues of the Z-methyl steroids employed as the starting steroids in ExamplesZ to 5, is productive of other 2-lower-alkyl 95: fiuoro-l1,8,17u,21-trihydroxy-4- pregnene-3",20 -diones, 2'-lower alkyl-9a-chloro-11B,17a,21- trihydroxy-4-pregnene-3,20-diones and 21-esters thereof wherein the lower-alkyl group is, for example, ethyl, propyl, butyl, amyl, hexyl, heptyl, or octyl. These compounds are oxidized in the manner disclosed in Example 6, to the corresponding ll-keto compounds.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. 2-lower-alkyl-9a-halo-1 1B, 17,2 l trihydroxy-4-pregnone-3,20-dione and 21-esters thereof represented by the following formula:

lower-alkyl wherein X is a halogen having an atomic weight from nineteen to 36, inclusive, and Ac is the acyl radical of carboxylic acid containing from one to twelve carbon atoms, inclusive.

3 2-rnethyl-9a-halo-1 1,6,17o -dihydroxy-2l-acyloxy. 4- rega e-3,20" dione' representea by the following formula? wherein X is a halogen having an atomic weight from nineteen to 36, inclusive, andA'c is the acyl radical of a hydrocarbon carboxylicjacid containing from one to twelve carbon atoms, inclusive. I

4. 2-methyl-9u-fluoro-11fi,17u-dihydroxy-21-acetoxy-4- pregnene-3,20-dione.

5. 2-lower-alkyl-9a-hallo-11,8,170:,21-trihydroxy-4-pregnene-3,20-dione represented by the following formula:

CHz-OH 11:0 i -OH lower-alkyl lower-alkyl wherein X is a halogen having an atomic weight from nineteen to 36, inclusive, and R is selected from the group consisting of hydrogen and the acyl radical of a wherein X is a halogen having an atomic weight from -nineteen to 36, inclusive, and Ac is the a'cyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

10. 2-lower-a'lkyl-9a-fiuoro-17a-hydroXy-21-acetoxy-4- pregame-3,1 1,20-trione.

11. 2-methyl-9a-fiuoro-17a-hydroxy-21-acetoxy-4-pregnene-3, 1 1,20-trione.

12. A compound represented by the formula:

13. 2 methyl 9mchloro 113,170 dihydroxy 21- acetoxy-4-pregnene-3,20-dione.

14. 2-methyl-9a-chloro-1 1 3,17m,2 1-trihydroxy-4 pregnene-3,20-dione.

15. 2-methyl-9a-fluoro-115,17a-dihydroxy 21 succinoxy-4-pregnene-3,20-dione, sodium salt represented by the following formula:

E0 1 F CH3 References Cited in the file of this patent UNITED STATES PATENTS Reichstein Apr. 11, 1950 Hogg et al. Jan. 10, 1956 Farrar et al Aug. 21, 1956 Fried et a1. Sept. 18, 1956 Sarett Jan. 29, 1957 Hogg et al. Apr. 30, 1957 Fried Sept. 16, 1958 OTHER REFERENCES J.A.C.S., vol. 75, pages 2273-4 1953 J.A.C.S., vol 76, page 1455 (1954) Experiential, vol. XII, No. 9, pages 325-331 (1956).

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,923,722 February 2, 1960 John A. Hogg et a1.

It is hereby certified that error appears in the printed specification of the above numbered atent requiring correction and that the said Letters Patent should read as correcte below.

Column 1, lines 69 to 72, Formula VI, the lower left-hand portion of the formula should appear as shown below instead of as in the patent:

iijj column 2, line 61, for lla-hydroxy read -11B-hydroxy-; column 9, line 31, for Examples 1 read -Example 1-; column 10, line 38, claim 5, for 9a-ha1lo read -9-halo-; lines 61 to 69, claim 8, the upper right-hand portion of the formula should appear as shown below instead of as in the patent:

column 11, lines 6 to 14, claim 9, the upper right-hand portion of the formula should appear as shown below instead of as m the patent:

Hr-Q-AO Signed and sealed this 9th day of August 1960.

Attest KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Ofiicer. Oomwm'ssz'omr of Patents. 

1. 2-LOWER-ALKYL-9A-HALO-11B,17A,21-TRIHYDROXY-4-PREGNENE-3,20-DIONE AND 21-ESTERS THEREOF REPRESENTED BY THE FOLLOWING FORMULA: 